Regulation of expression of the rodent cytosolic sulfotransferases.

Abstract

Understanding the molecular regulation of the sulfotransferases is important because these enzymes are essential to a number of critical biological processes. Sulfotransferase expression clearly plays a role in xenobiotic detoxication, carcinogen activation, prodrug processing, cellular signaling pathways, and the regulation of intratissue active androgen and estrogen levels. Although cytosolic sulfotransferases are present in the gut, adrenal, kidney, lung, skin, brain, and other extrahepatic tissues, the basis for the molecular regulation of this complicated gene family has been best characterized in the rat liver, where sulfotransferase levels are relatively abundant. Advances in genomic cloning and in the molecular characterization of individual sulfotransferase cDNAs have inspired new insights into the mechanisms involved in sulfotransferase gene regulation. In particular, the hypothalamic-pituitary-gonadal-adrenocortical axis appears to play a significant role in the regulation of individual sulfotransferase genes. The molecular signals that fluctuate with developmental age, gender, and the occurrence of systemic endocrinopathies also influence sulfotransferase gene expression. For example, diabetes, which disrupts glucose and ketone homeostasis, insulin sensitivity, gonadal and neuroendocrine hormone balance, protein kinase C isoform expression, and P450 metabolism, also disturbs hepatic sulfotransferase gene expression. What role does sulfotransferase expression play in target organ toxicity? Do xenobiotic-mediated changes in sulfotransferase expression compromise detoxication? Does deregulated sulfotransferase expression during development lead to birth defects by perturbing the delicate balance of active hormone levels in fetal tissues? Do conditions of glucocorticoid excess, such as stress or high-dose glucocorticoid therapy induce sulfotransferase expression and place toxicant and carcinogen bioactivation systems in overdrive? This review will summarize our current understanding of the molecular and cellular regulation of the major rodent cytosolic sulfotransferases. Only by thoroughly dissecting the regulation of this important multigene family in rodent liver, where sulfotransferase expression is most abundant, can we begin to focus on more pressing questions concerning the role of the sulfotransferases in the genesis of endocrinopathies and cancer in humans.